Classification rationale

PM1PM2PP3PP5 VUS

BRAF c.730A>C

The BRAF c.730A>C (p.Thr244Pro) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic, including an expert panel Pathogenic classification.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.² This missense change affects BRAF exon 6, a region specified by the RASopathy VCEP for PM1, and computational evidence supports a deleterious missense effect with REVEL 0.855, BayesDel 0.418359, and no major predicted splice effect by SpliceAI (maximum delta score 0.09).³

PM1 + PM2 + PP3 + PP5 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗revelbayesdelspliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001354609.1 · variants mapped to exon structure

BRAF NM_001354609.1

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 4

Strength Supporting Moderate Strong Very strong

PM1 moderate Pathogenic

This missense variant affects BRAF exon 6, which is a critical and well-established region specifically listed by the RASopathy VCEP for PM1 application.

Variant protein consequence p.(Thr244Pro)Variant maps to exon 6BRAF VCEP PM1 lists exon 6 as eligible region

cspec ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the RASopathy VCEP PM2 threshold requiring absence from controls.

Absent from gnomAD v2.1Absent from gnomAD v4.1

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PP3 supporting Pathogenic

Computational evidence supports a deleterious missense effect. REVEL is 0.855, which is above the RASopathy VCEP PP3 threshold of 0.7; BayesDel is also positive at 0.418359. SpliceAI predicts no major splice effect with a maximum delta score of 0.09, so the computational signal is consistent with a missense rather than splice mechanism.

REVEL 0.855BayesDel 0.418359SpliceAI max delta 0.09

cspec ↗spliceai ↗

PP5 supporting Pathogenic

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.

BRAF VCEP marks PP5 not applicableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 3 not met · 12 not assessed

Pathogenic

PS1 No evidence was identified that this variant produces the same amino acid change as a previously established pathogenic variant through a different nucleotide change, including the analogous BRAF/RAF1 provision in the RASopathy VCEP rules.

PS2 Published germline reports are linked for this variant, but the retrieved evidence does not provide case-level confirmation of de novo occurrence with confirmed maternity and paternity required for PS2 point assignment.

PS3 The RASopathy VCEP-approved functional study materials were reviewed, but no variant-specific approved assay result for p.(Thr244Pro) was identified in the retrieved evidence to support PS3 assignment.

PS4 This variant has been reported in ClinVar, including an expert panel Pathogenic classification, but the retrieved evidence does not provide the independent affected-case counts or point total required for RASopathy VCEP PS4 scoring.

PM5 No different pathogenic or likely pathogenic missense change at codon 244 was identified in the retrieved evidence, so PM5 could not be assigned from the materials reviewed.

PM6 Published germline reports are linked for this variant, but the retrieved evidence does not document an assumed or confirmed de novo occurrence with enough case-level detail to assign PM6 points.

PP1 No segregation data were identified showing this variant co-segregates with a RASopathy phenotype across informative meioses.

PP2 This is a missense variant in a gene where missense variation is clinically relevant, but the retrieved evidence does not provide the gnomAD missense z score needed for the BRAF RASopathy VCEP PP2 threshold (>3.09).

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is well below the BA1 threshold of 0.05% filtering allele frequency.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BS1 threshold of 0.025% filtering allele frequency.

BS2 No evidence was identified that this variant is present in unaffected individuals at a level that would contribute benign evidence under the RASopathy point-based framework.

BS4 No family data were identified showing lack of segregation of this variant with disease.

BP2 No evidence was identified that this variant occurs with another pathogenic RASopathy variant in a configuration that would support BP2 points.

BP4 Benign computational evidence is not supported.

BP5 No alternative molecular diagnosis or non-RASopathy explanation was identified that would support BP5 points.

N/A · 9 PVS1 · PM3 · PM4 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.855. BayesDel score = 0.418359.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRAF, an intracellular kinase, is frequently mutated in melanoma, thyroid and lung cancers among others.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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